The interplay of collagen IV, tumor necrosis factor-α, gelatinase B (matrix metalloprotease-9), and tissue inhibitor of metalloproteases-1 in the basal lamina regulates Sertoli cell-tight junction dynamics in the rat testis
The interplay of collagen IV, tumor necrosis factor-α, gelatinase B (matrix metalloprotease-9), and tissue inhibitor of metalloproteases-1 in the basal lamina regulates Sertoli cell-tight junction dynamics in the rat testis
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DOI：
10.1210/en.2002-220786
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发表时间：
2003-01-01
期刊：
影响因子：
4.8
通讯作者：
Cheng, CY
中科院分区：
文献类型：
--
作者：
Siu, MKY;Lee, WM;Cheng, CY
在精子发生过程中，前细线期和细线期精母细胞必须穿过由支持细胞间紧密连接（TJ）形成的血睾屏障，从邻近基底膜的生精上皮的基底室转移到第 VIII-IX 阶段的腔内室，以进一步发育。由于构成基底膜的细胞外基质 (ECM) 与血睾屏障非常接近，我们试图研究 ECM 在支持细胞 TJ 动力学中的作用。当体外培养支持细胞以启动支持细胞 TJ 通透性屏障的组装时，抗胶原 IV 抗体的存在确实扰乱了该屏障。由于已知 ECM 可以维持细胞因子库，并且 TNFα 已被证明可以调节其他上皮细胞中的 TJ 动态，因此我们研究了 TNFα 是否可以通过其对胶原蛋白 α3(IV) 和维持 ECM 稳态的其他蛋白质的影响来调节支持细胞 TJ 功能。正如预期的那样，重组 TNFα 在体外剂量依赖性地干扰支持细胞 TJ 屏障组装。 TNFα 还抑制occludin 的及时诱导，已知occludin 与支持细胞TJ 屏障组装有关。此外，TNFα诱导支持细胞胶原α3(IV)、明胶酶B(基质金属蛋白酶-9，MMP-9)和金属蛋白酶-1组织抑制剂的表达，但不诱导明胶酶A(基质金属蛋白酶-2)的表达，并促进pro-MMP-9的激活。因此，这些结果表明 TNFa 诱导的激活的 MMP-9 用于裂解 ECM 中现有的胶原蛋白网络，从而扰乱 W 屏障。这反过来又产生负反馈，导致 TNFα 诱导胶原蛋白 α3(IV) 和金属蛋白酶-1 组织抑制剂的表达，从而补充破坏的 TJ 屏障中的胶原蛋白网络并限制 MMP-9 的活性。总的来说，这些观察结果强化了这样的观点：ECM 除了在睾丸中的结构作用之外，还参与连接动力学的调节。
During spermatogenesis, preleptotene and leptotene spermatocytes must translocate across the blood-testis barrier formed by inter-Sertoli cell-tight junctions (TJs) from the basal compartment of the seminiferous epithelium adjacent to the basement membrane to the adluminal compartment at stages VIII-IX for further development. Because of the close proximity between extracellular matrix (ECM) that constitutes the basement membrane and the blood-testis barrier, we sought to investigate the role of ECM in Sertoli cell TJ dynamics. When Sertoli cells were cultured in vitro to initiate the assembly of the Sertoli cell TJ-permeability barrier, the presence of an anticollagen IV antibody indeed perturbed the barrier. Because ECM is known to maintain a pool of cytokines and TNFalpha has been shown to regulate TJ dynamics in other epithelia, we investigated whether TNFalpha can regulate Sertoli cell TJ function via its effects on collagen alpha3(IV) and other proteins that maintain the homeostasis of ECM. As expected, recombinant TNFalpha perturbed the Sertoli cell TJ-barrier assembly in vitro dose dependently. TNFalpha also inhibited the timely induction of occludin, which is known to associate with the Sertoli cell TJ-barrier assembly. Furthermore, TNFalpha induced the expression of Sertoli cell collagen alpha3(IV), gelatinase B (matrix metalloprotease-9, MMP-9) and tissue inhibitor of metalloproteases-1 but not gelatinase A (matrix metalloprotease-2), and promoted the activation of pro-MMP-9. These results thus suggest that the activated MMP-9 induced by TNFa is used to cleave the existing collagen network in the ECM, thereby perturbing the W-barrier. This in turn creates a negative feedback that causes TNFalpha to induce collagen alpha3(IV) and tissue inhibitor of metalloproteases-1 expression so as to replenish the collagen network in the disrupted TJ-barrier and limit the activity of MMP-9. Taken collectively, these observations strengthen the notion that ECM is involved in the regulation of junction dynamics in addition to its structural role in the testis.